6-fluoro steroids



United States Patent 6-FLUOR0 STEROIDS J Allan Campbell, Kalamazoo Township, Kalamazoo County, Raymond L. Pederson, Kalamazoo, John C. Babcock, Portage Township, Kalamazoo County, and John A. Hogg, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporationof Michigan No Drawing. Application November 29, 1957 Serial No. 699,502

29 Claims. (Cl. 260-23955) wherein R represents methyl or hydrogen, R represents hydrogen or an acyl, radical of, an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, and R 7 represents a lower aliphatic hydrocarbon radical. The term lower aliphatic hydrocarbon radical as used herein refers to an alkyl radical of from one to six carbon atoms, inclusive, e. g., methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl', and 3-methyl-penty1, or an alkynyl radical of the structure CECR3, wherein R is hydrogen or an alkyl radical of from one to four carbon atoms, inclusive,

e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,

and tertiary-butyl. v

It is an object of the present inventionto provide novel 6-fiu0ro-17B-hydroxy-17a-lower aliphatic hydrocarbon-4- ones, and the 17-acylates thereof, represented byFormula I I, are useful as starting materials for the production of anabolic agents with improved therapeutic ratio.

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other valuable compounds, represented by Formulas H, III, and IV, according to the following reactionsequence:

hydroxy-lh-lower aliphatic hydrocarbon androstan-3- ones and 6-fiuoro-17fii-hydroxy-17u-lower aliphatic hydrocarbon-l9-norandrostan-3-ones is accomplished by catalytic hydrogenation of the corresponding starting. compound of Formula I using a noble metal, preferably palladium, as catalyst. The reaction can be carried out at atmospheric or higher pressures and in the presence of an organic solvent, such as'ethyl acetate. The thusobtained. compounds of Formula III can then be treated with a metal borohydride, preferably an alkali metal borohydride, such as sodium borohydride, in the presence of an organic solvent, such as dioxahe, at room temperature, to produce the compounds of Formula IV, such as 6-fiuoro-3 3,17/3-dihydroxy-l7a-lower aliphatic hy drocarbon androstanes and 6-flnoro-3,B,l7fl-dihydroxyl'lcc-IOWfil aliphatic hydrocarbon 19-norandr0stanes.

The novel end products of this invention, the compounds of Formulal, possess useful therapeutic properties. The 6-fiuoro substituted l7a-alkyl compounds are For example, orally administered 60c-fillOIO-l7fi-hYd1OXY-l7amethyl-4-androsten-3-one (6a fluoro-l7-methyltestoster- Patented June 10, 1958 one) possesses marked anabolic activity and markedly lesser androgenic activity, having 2.25 times the anabolic activity and only 0.8 times the androgenic activity of orally administered 17/3-hydroxy-17u-methyl-4-androsten- 3 -one (methyltestosterone). subcutaneously administered 6a-fluoro-l7/3-hyd'roxy17a-methyl 4 androsten-3- one possesses 38 percent of the anabolic activity and only fourteen percent of the androgenic activity of subcutaneously administered 17fi-hydroxy-4-androsten-3-one l7- propionate (testosterone propionate). 6a-fluoro-17p3-hydroxy-17u-ethinyl-4-androsten-S -one (6a-fluoro-l7- ethinyltestosterone) and those. other compounds of Formulas'I, 11,111, and IV possessing the 170z-CECR grouping affect the secretion of gonadotropins and thus regulate ovulation and endometrial and placental development and, particularly when used in conjunction with estrogens, e. g., ethinylestradiol and/or androgens, e. g., Halotestin (9a-fluoro-llfl-hydroxy- 17 methyltosterone), reduce fertility, and constitute eifective therapy for dysmenorrhea, amenorrhea, endometriosis, threatened abortion and related gynocological disorders. When the compounds of Formulas II, III, and IV contain a 170:- alkyl side chain they possess the ability to modify the secretion of gonadotropins and in addition exhibit androgenic, anabolic and CNS-depressant activity. Administration of the steroids of Formulas I, II, III, and IV can be in conventional dosage forms such 'as pills, tablets, capsules, syrups, or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for injectable products.

Thenovel steroids of Formula I wherein R is an alkyl radical of from one to six carbon atoms, inclusive, e. g., methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, and 3-methylpentyl can be prepared according to the following reaction sequence:

V HO HO GHz R R VII VIII H0 O I no no I OH Ia O wherein R has the same meaning as previously given Ac represents the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive.

It is to be understood that in the reaction scheme depicted above and described in greater detail below in the body of the specification a radical of the structure C=- "CR wherein R is hydrogen or an alkyl radical of' from one to 'four carbon atoms, inclusive, e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl, can be substituted for the alkyl radical represented by R to produce the corresponding compounds having a -CECR .group, in the alpha position attached to the 17 carbon.

As indicated above and described in greater detail below, the reactions embodied in this method of the invention are susceptible of variation in the specific steps leading to the products, 6a-fluoro-l7fl-hydroxy-l7a alkyl-4- androsten-3-ones and 6u-fluoro-17B-hydroxy-l7a-alkyl-4- (l9-norandrostcn) -3-ones, represented by Formula Inc, and 6,8-fluoro-17fl hydroxy-17a-alkyl-4-androsten-3-ones and 6B-fluoro-17B-hydroxy-17a-alkyl-4 (19 norandrosten)-3-ones, represented by Formula 1;? (or if desired the l7-acy1ates of the compounds of I00 and 1,8, represented by Formulas XHu and XIIfi, respectively), the precise sequence selected being determined by such factors as economics and convenience.

One of the processes of the present invention comprises allowing compounds of the type represented by Formula V, such as 3B,l7fi-dihydroxy-l7a-alkyl-5-androstenes and 3,6,l7fl-dihydroxy-17a-alkyl-5-(19-norandrostenes), to react with a peracid such as peracetic or perbenzoic acid to obtain the corresponding 5,6-epoxy compounds represented by Formula VI, such as 3 3,171?- dihydroxy-17a-alkyl-5a,6a-epoxyandrostanes and 3fi,17;8- dihydroxy-17a-alkyl-5a,6a-epoxy-19-norandrostanes.

The thus-obtained compounds of Formula VI, such as the 50:,6oc-6P0XY compounds, are then treated with a fluorinating agent such as anhydrous hydrogen fluoride in the presence of an organic solvent, preferably a mixture of chloroform and tetrahydrofuran, to obtain the compounds of Formula VII, such as 6}3-fluoro-3/8,5oz,l7/3-trihydroxy 17a alkylandrostanes and 6]3fll1OIO-3fi,5a,l7}3- trihydroxy-lh-alkyl-l9-norandrostanes.

The compounds of Formula VII are then oxidized, preferably in acetic acid solution, with an oxidizing agent, such as chromic anhydride or sodium dichromate, using a slight excess of the oxidizing agent. At the conclusion of the desired oxidation reaction, the chromic acid oxidant is preferably destroyed by addition of methyl alcohol, ethyl alcohol, and the like. Thereafter, the resulting compounds of Formula VIII, such as 6 8-fiuoro- 501,175 dihydroxy 17oz a;1ky1androstan 3 ones and 613 fluoro 5a,l7}8 dihydroxy 17a alkyl 19 norandrostan-3-ones are recovered by conventional means such as precipitation with water, dilution with water and extraction with a water-immiscible solvent, e. g., methylene chloride, benzene, ether, or the like, following by evaporation of the solvent.

The compounds of Formula VIII, such as 6fi-fluoro- 5a,17p-- dihydroxy 17o: alkylandrostan 3 ones and 6,3 l flu'or'o sum aiiiydiox 17oz allryl 19 norandrostan-3-ones are then dehydrated, in the presence of an organic solvent, such as ethyl alcohol, with mild conditions using a base, such as sodium hydroxide. This reaction is productive, of the compounds of Formula I18, such as 6B-fluoro-17p-hydroxy 17a alkyl 4 androsten-B-ones and 6fl-fluoro-17[3-hydroxy-l7a-alkyl-4-(19- norandrosten) -3 -ones.

The thus obtained GB-fiuoro compounds are then isomerized to the corresponding 6a-fiuoro compounds of androsten-B-ones and tint-fluoro-l7fl-hydroxy-l7a-alkyl- 4-(l9-norandrosten) 3 -ones by treating the 6fi-fluoro compounds, at temperatures of Zero degrees Centigrade or slightly lower, in a liquid medium such as an organic solvent, for example, chloroform, methylene chloride, ether, and the like, and in the presence of a prototropic agent (a proton donating agent) such as Water, alcohols, organic acids, and the like, with a mineral acid such as hydrochloric acid. The reaction mixture can then be washed with successive portions of dilute alkali, such as sodium bicarbonate, and water, and evaporated to obtain the 6a-fluoro compounds of Formula Ia.

Alternatively, the fiat-fiHOIO compounds of Formula Ia can be obtained directly from the compounds of Formula VIII by a combined dehydration, isomerization reaction. This reaction is carried out by treating the compounds of Formula VIII with a mineral acid such as hydrochloric acid. The reaction is carried out in a liquid medium suchas an organic solvent, for example, chloroform, methylene chloride, ether, and the like, and in the presence of a prototropic agent (a proton donating agent), such as water, alcohols, and organic acids while maintaining the temperature at zero degrees centigrade or slightly lower, Advantageously, such temperatures should be maintained throughout the period of contact with the acid.

The l7-acylates represented by Formula XIIa and XIIB are obtainable by allowing the compounds of Formulas Ia and I5, respectively, to react with the anhydride of an organic carboxylic acid, particularly a hydrocarbon carboxylic acid, containing from one to twelve carbons, inclusive, for example, a saturated straight-chain aliphatic acid, e. g., acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, a cycloaliphatic saturated acid, e. g., cycloheXane-carboxylic, an

' alkaryl acid, e. g., benzoic, phenylacetic, .2-phenylpropionic, o-, m-, and p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e. g., sodium, salts), e. g., succinic, adipic, a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, cinnamic, "a dibasic unsaturated acid (which can be converted into water-soluble, e., g., sodium, salts), e. g., maleic and citraconic.

The GB-fluoro compounds of Formula XIIfl can be converted to the corresponding 6a-fluoro compounds of Formula XII, such as 6e-fluoro-l7fl-hydroxy-l7a-alkyl- 4-androsten-3-one l7-acyl'ates and 6d-fiuoro-l7fi3-hydtoxyl7a-alkyl-4 (l9-norandrosten)-3-one l7-a-cylates by the same method used to convert the compounds of Formula 1,6 to the compounds of Formula Ia.

Alternatively, the compounds of Formula VIII can be produced according to the following reaction sequence:

in which R and R have the same meaning as previously given and R is an alkylene radical containing not more than eight carbon atoms, inclusive, and the attachingoxygen to carbon bonds are separated by a chain of at least two and not more than three carbon atoms.

The obtention of the compounds of Formula VIII by the alternative route given above comprises treating the compounds of Formula IX, such as 17,8-hydroXy-17ualkyl 4 androsten 3 ones and 175 hydroxy 17aalkyl-4-(l9-norandrosten)-3-ones, with ethylene glycol, in the presence of a strong acid such as toluenesulfonic acid, orthochlorobenzenesulfonic acid, sulfuric acid, and the like, to produce the compounds of Formula X, such as 17 3 hydroxy 17cc alkyl 5 androsten 3 one 3-ethylene ketals and 17/3-hydroxy-l7a-alkyl-5-(l9-norandrosten)-3-one B-ethylene ketals. Similarly the compounds of Formula IX can be allowed to react with other 1,2a1kane diols or 1,3-alkane diols such as propylene glycol, butane-1,2-diol, butane-1,3-diol, pentane- 1,2- and 1,3-diol, hexane-1,2- and 1,3-diol, heptane-1,2- and 1,3-diol, octane-1,2- and 1,3-diol, or other alkane diols of the formula:

and wherein the total number of carbon atoms in the alkane diol is up to and including eight carbon atoms, to obtain the corresponding 3-alkylene ketals of Formula X.

The compounds of Formula X are then treated with a peracid, such as peracetic or perbenzoic acid, which is productive of the compounds of Formula XI, such as 176 hydroxy a alkyl 5a,6u epoxyandrostan-3- one 3-ethylene ketals and l76-hydroxy-17a-alkyl-5a,6a epoxy-l9 norandrostan-3-one 3-ethylene ketals. The thusobtained compounds of Formula XI can then be treated with hydrogen fluoride to obtain the compounds represented by Formula VIII, such as 6,8-fluoro-5ot,l718-dihydroxy 17a alkylandrostan 3 ones and 6p fluoro- 5 a, l7p-dihydroxyl 7a-alkyll 9-norandrostan-3-ones.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 A. 33,175-dz'hydr0xy-l 7a-methyl-5a,6a-ep0xyandr0stane (compound V14!) 32 grams of 3B,l7B-dihydroxy-l7a-methyl-5-androstene, compound Va, and four grams of sodium acetate were dissolved in 1000 milliliters of chloroform and cooled to fifteen degrees centigrade. To the thus-obtained solution there was added, over a five minute period, forty milliliters of forty percent peracetic acid whilst stirring and cooling. The reaction mixture was allowed to stand for thirty minutes and then warmed to about 25 degrees centigrade. After three hours, 500 milliliters of water was added thereto. The mixture was then filtered to recover the precipitate contained therein. The precipitate was washed with water and dried to yield 23.45

B. 6B-fluoro-3/3,5u,l 7B-trihydr0xy-1 7 a-methylandrostane (compound Vlla) 13.2 grams of anhydrous hydrogen fluoride was condensed in a IOO- milliliter polyethylene bottle using a dry ice-cooling bath. Forty milliliters of precooled chloroform was then added, followed by the cautious addition of 24 milliliters of tetrahydrofuran. To this cold solution there was then added nine grams of compound Via. The reaction mixture thus obtained was warmed to about minus fifteen degrees centigrade for three and one-half hours and then poured slowly into 900 milliliters of ice water containing sixty grams of sodium bicarbonate. To the aqueous mixture there was then added 300 milliliters of methylene chloride. The mixture was shaken and upon standing an aqueous and a methylene chloride layer separated. The methylene chloride layer was drawn oif and saved. The aqueous layer was filtered and the filtrate obtained was extracted with another 300-milliliter portion of methylene chloride. The extraction procedure was repeated a third time using another 300-milliliter portion of methylene chloride. The methylene chloride extracts obtained in the three extractions were then combined, washed with water, dried and evaporated to a solid residue. Recrystallization from acetone gave 3.1 grams of 6/3-fluoro-3fi,5a,17p-trihydroxy-17u-methylandrostane, compound VIIa, melting at 230-232 degrees centigrade and having an [oil minus 26 degrees (0.96%, pyridine).

Analysis.-Calcd. for C H FO F, 5.58. Found: F, 5.06.

C. 6fi-flu0ro-5a,17ii-dihydroxy 17o: methylandrostan-3- one (compound VlIIa) To an ice-bath-cooled solution of 2.82 grams of chromic anhydride, 118 milliliters of acetic acid and three milliliters of water, there was added, whilst stirring and cooling, 7.9 grams of compound VIIa. After standing for fifteen minutes, the reaction mixture was warmed to about 25 degrees centigrade and allowed to stand for two and one-half hours. To the reaction mixture there was then added ten milliliters of methyl alcohol and 300 milliliters of water, the addition of the latter causing a solid to precipitate. The precipitate was collected and washed with water to give 4.9 grams of crude compound VIIIa, one gram of which was recrystallized from acetone-Skellysolve B hexanes to give 0.51 grams of 6,8- fluoro-5u,17fi-dihydroxy-17amethylandrostan-3-one, comcompound VIIIa, melting at 239-241 degrees centigrade and having an [:11 minus ten degrees (0.86%, CHCl Analysis.Calcd. for C H FO C, 70.97; H, 9.23; F, 5.61. Found: C, 70.61; H, 9.22; F, 6.20.

D. 6/3-flu0r0-1 7/8-hydr0xy-1 7 u-methy l-4 -andr0sten-3 -one (6,8-flu0r0-1 7 methyltestosterone) (compound I flu) 11.3 grams of compound VIIIa were dissolved in 350 milliliters of absolute ethyl alcohol and cooled to fifteen degrees centigrade. Forty milliliters of 0.1 N sodium hydroxide were then added to the solution which was then cooled to five degrees centigrade. After standing atfive degrees centigrade for sixteen hours the solution was neutralized with four milliliters of acetic acid and concentrated at reduced pressure until crystallization of unreacted compound VIIIa began. The mixture was chilled and filtered to collect the precipitate of compound VIIIa which had formed. The filtrate was retained. The precipitate was then recrystallized from acetone and filtered to give five grams of compound Villa. The acetone filtrate was combined with the first obtained filtrate and concentrated to a dry residue which was then dissolvedin methylene chloride. The thus-obtained solution was then absorbed on 200 grams of synthetic magnesium silicate (Florisil) and eluted, using 200-milliliter fractions, as follows:

Fractions 1-9-acetone:Skellysolve B hexaneszz4z96 Fractions 1025-acetone:Skellysolve B hexaneszz5 Fractions 1022 were combined and crystallized to give 2.26 grams of material. Recrystallization from acetone gave 2.02 grams of 6B-fluoro-17fi-hydroxy-l7a-methyl-4- androsten-3-one, compound Ifla; melting point 164-165 degrees centigrade, [ml minus 28 degrees (0.985%, CHCl h 235 m (log a 4.09).

Analysis.Calcd. for C H FO C, 74.96; H, 9.12; F, 5.93. Found: C, 75.15; H, 9.31; F, 5.64.

E. 6a-fluor0-17fi-hydroxy-1 70-methyl-4-androsten-3-0ne- (6a-fluor0-1 7-methyltest0ster0ne) (compound Iaa) A solution containing 1.1 grams of compound Ifia dissolved in twenty milliliters of reagent grade chloroform (containing traces of alcohol) was cooled to minus ten degrees centigrade. Anhydrous hydrogen chloride was passed through the solution for forty minutes, whilst cooling in an ice-salt bath, followed by a stream of nitrogen for twenty minutes. The solution was then washed with a cold five percent sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to a residue. Crystallization from acetone-Skellysolve B hexanes gave 0.31 gram of 6oc-flu01O-17fl-hYd1'OXY-17amethyl-4-androsten3-one, compound Iaa; melting point 155-157 degrees centigrade (melting point on admixture with the 6,8-isomer, compound Ifla, was depressed to 133135 degrees centigrade), x 237 m (log a 4.13).

Analysis.Calcd. for C H FO C, 74.96; H, 9.12; F, 5.93. Found: C, 74.01; H, 9.03; F, 5.77.

F. 60: fluoro-1 7fl-hydr0xy-1 7u-methyL4-andrOsten-3-one 17-acetate (6u-fluor0 17 methyltestosterone acetate) (compound Xllcza) One gram of compound load was dissolved in nine milliliters of acetic anhydride and warmed under reflux for one-half hour. The reaction mixture was then distilled under reduced pressure to remove unreacted acetic anhydride. The crystalline material, 6a-fiuoro-17fl-hydr0xy- 17a-methyl-4 androsten 3 one 17 acetate, compound Xlltuz, remaining after the distillation was then recrystallized from aqueous methanol.

Similarly, by reacting compound Illa with the appropriate hydrocarbon carboxylic acid anhydride, for example, at temperatures between and degrees centigrade, there are produced other 17-acylates of 6afluoro-17fi-hydroxy-17a-methyl-4-androsten-3-one such as 6ot-fiuoro-l7fi-hydroxy 17a methyl 4 androsten-3-one 17-propionate, 6oc-flll01'0 17B-hydroxy-17a-methyl-4-androsten-3-one 17-butyrate, 6oz fluoro 17fl-hydroxy-17amethyl-4-androsten-3-one 17-valerate, 6a-fiuoro-17fi-hydroxy-l7a-methyl-4-androsten-3-one 17-hexanoate, 6ozfiuoro-17fi-hydroxy-17a methyl 4 androsten-3-one 17- laurate, 6a-fiuoro-17B-hydroxy-17a-methyl-4-androsten- 3-one 17-trimethylacetate, Got-fluoro-17fl-hydroxy-17amethyl-4-androsten-3-one 17-isobutyrate, 6oc-fl1l01'0-17fihydroxy-17a-methyl-4-androsten-3-one 17-isovalerate, 60!.- fluoro 17fi-hydroxy-17a methyl-4-androsten 3-one 17- cyclohexanecarboxylate, 6a fluoro 17/3 hydroxy 17amethyl-4-androsten-3-one l7-benzoate, 6a-fluoro-17/3-hydroxy-17a-methyl-4-androsten-3-one 17-phenylacetate, 6afluoro-l7fi-hydroxy-17a-methyl-4-androsten-3-one 17-(flphenylpropionate), Got-fluoro-17/3-hydroxy-17a-methyl-4- androsten-3-one 17-(o-, m-, p-toluate), 6a-fiuoro-l75-hydroxy-17a methyl-4-androsten-3 one l7-he1nisuccinate, fia-fiuoro-l7fl-hydroxy-17a-methyl-4-androsten-3-or1e 17- hemiadipatc, 6a-fluoro-17f3-hydroxy-17a-methyl-4-androsten-3-one 17-acrylate, 6a-fiuoro-l7fl-hydroxy-l7a-methyl- 4-androsten-3-one 17-crotonate, 6a-fluoro-17B-hydroxy- 17a-methyl-4-androsten-3-one 17-undecylenate, 6a-fil101'0- 17fl-hydroxy-17a-methyl-4-androsten-3-one 17-propionate.

6a-fiuoro-17,B-hydroxy-17wmethyl-4-androsten-3 -one 17-,

cinnamate, 6a-fluoro-l7fi-hydroxy-l7u-methyl-4-androsten-3-one 17-maleate, and Got-fluoro-17,6-hydroxy-17amethyl-4-androsten-3-one 17-citraconate.

Similarly, 6B-fluoro-17,8-hydroxy-17u-rnethyl-4-androsten-3-one, compound Ilia, is reacted with acetic anhydride to obtain the corresponding 17-acetate, compound XIIfia, which is then converted to 6a-fiuoro-17/3-hydroxy17amethyl-4-androsten-3-one 17-acetate, compound XIIaa, using the procedure set forth in Example 1, part E.

7 Substituting a stoichiometric equivalent of 3fl,17fldihydroxy-17a-ethyl5-androstene as the starting material in place of 35,17B-dihydroxy-17a-methyl-5-androstene and following the procedure of Example 1,'there is produced, in consecutive order, 3,8,17fi-dihydroxy-17a-ethyl- 5u,6a-epoxyandrostane (part A), 6/3-fluoro-3fl,5ot,l7;3-trihydroxy-l7ot-ethylandrostane (part B), 6fi-fluoro-5a,l7B- dihydroxy-l7u-ethylandrostan-3-one (part C), GB-fiuoro- 17B-hydroxy-l7u-ethyl-4-androsten-3-one (part D), 60cfluoro-l7/3-hydroxy-17a-ethyl-4-androsten-3-one (part E), and 6a-fiuoro-17fl-hydroxy-17a-ethyl 4-androsten-3-one 17-acetate.

EXAMPLE 2 60t-flLlOl0-1 7,8 hydroxy-Z 7 a methyl 4 andrsten-3-0ne (compound I ma) directly from 6/3-fluoro-5a,17B-dihydroxy-J 7u-methylandrostan-3-one (compound VIIIa) The procedure of Example 1, parts A through C, was followed to produce compound VIIIa, four grams of which were dissolved in 300 milliliters of reagent grade chloroform (containing traces of alcohol) and cooled to minusten degrees centigrade. Anhydrous hydrogen chloride gas was bubbled through the solution for two and one-half hours whilst maintaining the temperature at minus ten degrees centigrade. The reaction mixture was then washed with water, cold five percent sodium bicarbonate solution and againwith water. The washed reaction mixture was then dried oversodium sulfate, followed by distillation of the chloroform to give a residue. To the residue there was added eighty milliliters of methylene chloride and eighty milliliters of Skellysolve B hexanes to give a solution which was then adsorbed on 200 grams of Florisil, and eluted, using 230- milliliter fractions, as follows:

Fractions 116-acetone-Skellysolve B hexanes:: :95. Fractions 1730-acetone-Skellysolve B hexanes::6:94.

, Fractions 1430 were combined to give 2.42 grams of material. Recrystallization from methylene chloride and Skellysolve B hexanes gave 1.85 grams of 6u-fluoro-17B- hydroxy-17a-methyl-4-androsten-3-one, compound Iaa; melting point 161-163 degrees centigrade, lal plus 72 degrees (1.01%, CHCl A 236.5 mg (log 4.18).

Analysis.-Calcd. for C H FO F, 5.93. Found: F, 5.83.

EXAMPLE 3 6 ot-flLlOIO-I 7/3-hydr0xy-1 7a-methyl-4-(19-norandrosten) -3- one (du-fluoro-I7ot-methyl-19-nortestosterone) and the J7-acetute thereof (compounds lab and XlIocb, respectively) Following the procedure of Example 7, parts A through E, but using 3B,17B-dihydroxy-17a-methyl-5-(19-norandrostene) compound Vb, as the starting material, there is obtained 6a-fluoro-17fl-hydroxy-17a-methy1-4-(19-norandrosten)-3-one, compound Iocb, which is treated in the manner disclosed in Example 1, part F, to obtain 60:- fluoro-l7 3 hydroxy-lh-methyl 4-(19 norandrosten)- 3-one 17-acetate, compound XIIocb.

Compound Vb used as the starting material is prepared by treating the known compound 17B-hydroxy-17u-methyl 4-(19-n0randrosten)-3-one [see Djerassi et al., J. A. C. 8., vol. 76, p. 4092-4 (1954)], according to the procedure disclosed in U. S. Patent 2,798,879 (note particularly Example 2) to obtain the 3-enolacetate of 17,8-hydroxy-' 17u-methy1 4 (l9- norandrosten)-3-one 17-acetate [3,8, 17 p dihydroxy 17 a-methyl-3,5-(l9-norandrostadiene) 3,

l7-diacetal]. The latter compound is then subjected to treatment with sodium borohydride, followed by treatment with alkali, according to the procedure disclosed by Hart man, J. A. C. 8., vol. 77, p. 5151-54 (1955) to produce 3 p, 17 p-dihydroxy- 1 7a-methyl-5 1 9-norandrostene).

EXAMPLE 4 dot-fluoro-l 7/3-methyl-4-(19-norandrosten) 3 one (compound lab) directly from 6,8-flu0r0-5u,17fl-dihydroxy-J 1 7u-methyl-19-norundrostan-3-one (compound VIII b) Following the procedure of Example 1, parts A through C, but using compound Vb as the starting material, there is obtained 6,8-fiuoro-5a,l7fi-dihydroxy 17a methyl-l9- norandrostan-S-one, compound VIIIb, which is treated with anhydrous hydrogen chloride in the manner disclosed in Example 2 to obtain 6ut-fluoro-l7p-hydroxy-l7cx-methyl- 4-(l9-norandrosten)-3-one, compound lab.

EXAMPLE 5 A. 3 8,17B-dihydroxy-17a-ethinyl-5a,6ot-ep0xyandrostane (compound Vlc) T o a solution of 0.80 gram of 3,3,17/3-dihydroxy-17aethinyl-S-androstene dissolved in eighty milliliters of chloroform there was added 0.10 gram of anhydrous sodium acetate- The mixture was stirred for one hour and then cooled to about eight degrees centigrade. There was then added 0.72 milliliter (5.5 millimoles) of a forty percent peracetic acidsolution. The reaction mixture was stirred for five minutes followingthe addition of the peracetic acid and then allowed to stand for sixteen hours at five degrees centigrade. Titration of the reaction mixture showed that 1.1 equivalents of the peracetic acid added B. 6 ,8-flu0ro-3 5,5 a-I 7/3-17171 ydrowy-I 7a-ethinylandrostane (compound V IIc) 2.5 grams of anhydrous hydrogen fluoride was condensed in a -rnilliliter polyethylene bottle using a Dry Ice-acetone cooling bath. Fifteen milliliters of pre-cooled chloroform was then added, followed by the cautious addition of five milliliters of tetrahydrofuran. solution there was then added 1.8 grams of compound VIc.

then warmed to five degrees centigrade, at which temperature it was held for one hour. The reaction mixture was poured into ice Water, containing excess sodium bicarbonate, forming an aqueous layer and an organic layer containing a crystalline solid. The organic layer was separated and diluted with chloroform and the crystals in the organic chloroformic layer were isolated. The crystals thus obtained were Washed and dried to give 0.65 gram of 6/3-fiuoro-3B,5a,17,6-trihydroxy 17a ethinylandrostane, compound VIIc, melting at 244 degrees centigrade with decomposition.

Analysis.-Calcd. for C H FO C, 71.96; H, 8.92; F, 5.42. Found: C, 72.37; H, 9.19; F, 4.43.

To a solution of 0.55 gram of compound VIIc in three milliliters of pyridine there was added a slurry'containing To this cold.

The thus-obtained reaction mixture was kept at about minus fifteen degrees centigrade for one hour and "11 0.55 gram of chromic anhydride in eight milliliters of pyridine. The reaction was stirred overnight at room temperature and then the pyridine was blown off under a stream of nitrogen. The residue thus obtained was slurried with brine and extracted with ethyl acetate. The ethyl acetate solution was washed with brine and water and then dried. The ethyl acetate was removed leaving a solid residue which was recrystallized from acetoneether to yield 100 milligrams of 6;3-fluo ro-a,l7fi-dihydroxy-l7a-ethinyl-androstan 3 one, compound VIIIc, melting at 258-259 degrees centigrade with decomposition. Infrared analysis showed OH bands at 3620 and 3410 cm.- ECH at 3300 CID-"1, CEC at 2120 GEL-'1, and C=O at 1700 cm.*.

D. 6 0c fluoro-I7B-hydroxy-17a-ethinyl-4-androsten-3-0ne (6a-flu0r0-17-ethinyltestoster0ne) (compound I are) and 6/3-flu0r0-17B-hydr0xy-17a-ethinyl 4 androsten-S-one (6 fi-fluoro-I 7-ethinyltest0ster0ne) (compound I Be) A solution containing 150 milligrams of compound VIIIc, eight milliliters of chloroform and 0.5 milliliter of absolute ethanol, cooled in an ice-salt bath, was saturated with gaseous hydrogen chloride. After a half-hour nitrogen was bubbled through the solution to remove some of the hydrogen chloride. The solution was washed three times with water, dried and the chloroform removed by evaporation. The residue remaining was taken up in methylene chloride and poured onto a 45-grarn magnesium silicate (Florisil) column packed wet with Skellysolve B hexanes. The column was then washed with increasing amounts of acetone in Skellysolve B hexanes. The eluates were collected in 100-milliliter fractions. Fractions 11, 12 and 13 were crystallized following elution with eight percent acetone in Skellysolve B hexanes. Recrystallization from acetone-Skellysolve B hexanes gave 10.8 milligrams of 6B-fluoro-17B-hydroxy-17a-ethinyl-4 androsten-3-one, compound I180; melting point 245-247 degrees centigrade with decomposition, k fi 234 m [ad minus 57 degrees (CHCl Fraction 14 was a mixture of compounds Iac and I/ic.

Fractions 15-21 were crystallized following elution with eight to ten percent acetone in Skellysolve B hexanes. Recrystallization from acetone gave 62 milligrams of 6afiuoro l7fi hydroxy-17a-ethinyl-4-androsten-3-one, compound Imc; melting point 237-239 degrees centigrade, A 236 m a 14,675, [ab plus thirty degrees (CHCl Analysis.-Calcd. for C21H27FO2: C, 76.23; H, 8.24; F, 5.75. Found: C, 76.41; H, 8.34; F, 4.88.

E. fifi-fluoro-l7,8-hydr0xy-17a-ethinyl-4-androsten-3-0ne (compound 130) By treating compound VIIIc according to the procedure disclosed in Example 1, part D, there is obtained 6/9- fiuoro-17p-hydroxy-17a-ethinyl-4-androsten-3-one (compound I180).

F. 6 a-fluoro-I 7fl-hydroxy-17a-ethinyl-4-androsten-3- one (compound I ac) By treating compound LBc according to the procedure disclosed in Example 1, part B, there is obtained 6a-fiuoro 175-hydroxy-17a-ethinyl-4-androsten-3-one (compound lac).

G. 6a-flu0r0-17 3-hydr0xy-1 7oc-ethinyl-4-andr0sten-3-0ne l 7-acetate (6a-flu0r0-17-ethinyltest0sterone acetate) (compound Xllac) By treating Iotc according to the procedure disclosed in Example 1, part F, there is obtained 6a-fluoro-17flhydroxy-17a'ethinyl-4-androsten-3-one 17-acetate.

In like manner, other 17-acylates of compound Iac are produced by reaction with the appropriate hydrocarbon carboxylic acid anhydrides, following the procedure disclosed in Example 1, part F.

Similarly, compound I/Sc is allowed to react with acetic anhydride to obtain 6,3-fiuoro-17fl-hydroxy-17e-ethinyl- 4-androsten-3-one 17-acetate, compound XIIBc, which is then converted to compound XIIaC, using the procedure set forth in Example 1, part E.

Substituting a stoichiometric equivalent of 3,8,17,8-dihydroxy-l7a-methylethinyl-S-androstene as the starting material and following the procedure of Example 5, parts A through D, there is obtained 6a-flu0r0-17fil-hydr0Xy- 17a-methylethinyl-4-androsten-3-one and 6,3-fluoro-17flhydroxy-17a-methylethinyl-4-androsten-3-one. Alternatively, by following the procedure of Example 5, parts A through C, and treating the compound thus obtained, 6,8-fluoro-5a,17fi-dihydroxy-17a-methylethinylandrostan-3-one, according to the procedure disclosed in Example 1, part D, there is produced 6;8-fluoro-17/3-hydroxy-17a-methylethinyl-4-androsten-3-one. The latter compound is then converted to 6a-fluoro-17B-hydroxy- 17a-methylethinyl-4-androsten-3-one by following the procedure of Example 1, part E. 6tt-fiuoro-l7fl-hydroxy-17amethylethinyl-4-androsten-3-one is then converted to the 17-acetate thereof by following the procedure of Example 1, part F.

The starting compound, 3B,17p-dihydroxy-17a-methylethinyl-S-androstene, is prepared from 3,8-hydroxy-5-androsten-17-one (dehydroepiandrosterone) by substituting methyl acetylene for acetylene in the procedure disclosed by Ruzicka et al., Helv. Chim. Acta, vol. 20, p. 1280 (1937).

A EXAMPLE 6 6a fluoro hydroxy 17a ethinyl 4 androsten 3-one (compound lac) directly from 6 3-flu0r0-5a,1713

dihydroxy 17a ethinylandrostan 3 one (compound VIIlc) The procedure of Example 5, parts A through C, is followed to produce compound VIIIc; By treating compound VIIIc according to the procedure disclosed in Example 2 there is produced 6a-fluoro-17fi-hydroxy-17a.- ethinyl-4-androsten-3-one (compound Iac).

EXAMPLE 7 6a fluoro 17,3 hydroxy 17a ethinyl 4 (19 noran drosten) -3-one (6 a-fluoro-l 7oc-ethinyl-19-n0rtestosterone) and the 17-acetate thereof (compounds Iad and Xllad, respectively) Following the proceduce of Example 5, parts A through D (or Example 5, parts A through C, followed by the procedure of Example 1, parts D and E), but using 313, 17p-dihydroxy-17a-ethiny1-5-( 19-norandrostene) compound Vd, as the starting material, there is obtained 6a.- fiuoro 17/3 hydroxy 17a ethinyl 4 (19 norandrosten)'-3-one, compound Iad, which is treated in the manner disclosed in Example 1, part F, to obtain 6tz-fl1101'0- l7fl-hydroxy-l7a-ethinyl-4-( l9-norandrosten) -3-one 17- acetate, compound XIIad.

'Compound Va used as the starting material is prepared by treating the known compound 17B-hydroxy-17methinyl-4-(19-norandrosten)-3-one (see U. S. Patent 2,- 702,811, noting particularly Example 3), according to the procedure disclosed in U. S. Patent 2,798,879 (note particularly Example 2) to obtain the 3-enol acetate of 17phydroxy-17a-ethinyl-4-( 19-norandrosten) -3-one 17-acetate [3B,17fi-dihydroxy-17a-ethinyl-3,5-(19-norandrostadiene)-3,17-diacetate]. The latter compound is then subjected to treatment with sodium borohydride, followed by treatment with alkali, according to the procedure disclosed by Hartman, J. A. C. 8., vol. 77, p. 5151-54 (1955) to produce 313,17fl-dihydroxy-17a-ethinyl-5-(19- norandrostene) Substituting a stoichiometric equivalent of 3 13,1713-dihydroxy-17a-methylethinyl-5-(19-norandrostene) as the starting material and following the procedure of Example 5, parts A through D, there is obtained 6a-flu0l0-1713- 13 hydroxy 17a. methylethinyl 4 (19 norandrosteri): 3-one and 6B-fluoro-17fl-hydroxy-17d-methylethinyl-4- (l9-norandrosten)-3-one. Alternatively, by following the procedure of Example 5, parts A through C, and treating the compound thus obtained, 6 8-fluoro-5a,17fi-dihydroxy- 17a-methylethinyl-19-norandrostan-3-one, according to the procedure disclosed in Example 1, part D, there is produced Gp-fluoro-17,8-hydroxy-l7a-methylethinyl-4- (19-norandrosten)-3-one. The latter compound is then converted to 6a-fluoro-17B-hydroxy-17a-methylethinyl-4- (l9-norandrosten)- 3-one by following the procedure of Example 1, part E. 6a-fluoro-17/8-hydroxy-l7u-methylethiny1-4-(19-norandrosten)-3 one is then converted to the 17-acetate thereof by following the procedure of Example 1, part F.

The starting compound, 3e,17,8-dihydroxy-l7a-methylethiny1-5-( l9-norandrostene) is prepared in the following manner: a stoichiometric equivalent amount of methylacetylene, in place of acetylene, is allowed to react With 19-norandrostenedione according to the procedure disclosed in U. S. Patent 2,744,122, to produce the progestational compound 1718-hydroxy-17a-methy1ethiny1-4-(19- norandrosten) -3-one. The latter compound is treated according to the procedure disclosed in U. S. Patent 2,798,- 879 (note particularly Example 2) to obtain the 3-enol acetate of 17B-hydroxy-17a-methylethinyl-4-(19-norandrosten)-3-one 17-acetate which is then subjected to treatment with sodium borohydride, followed by treatment with alkali, according to the procedure disclosed by Hartman, J. A. C. 8., vol. 77, p. 5151-54 (1955) to produce 35, 17/3-dihydroxy-17a-methylethinyl-5-( 19-norandrostene) It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 6-fiuoro-17 3-hydroxy-17a-alkyl-4-androsten-3-ones of the following formula:

wherein R is selected from the group consisting of methyl and hydrogen, R is an alkyl radical containing from one to six carbon atoms, inclusive, and R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

2. 6-fluoro-1718-hydroxy-l7u-alkyl-4-androsten-3-one in which the alkyl radical contains from one to six carbon atoms, inclusive.

3. 6-fluoro-17fl-hydroxy-17a-alkyl-4-androsten-S-one 17- acylates in which the alkyl radical contains from one to six carbon atoms, inclusive, and the acyl radical is that of a hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive.

4. 6-fluoro-17fl-hydroxy-17a-methy1-4-androsten-3-one.

5. 6-fluoro-17 3-hydroxy-17a-methyl-4-androsten-3-one 17-acetate.

6. 6-fluoro-17fl-hydroxy-l7a-ethyl-4-androsten-3-one.

7. 6-fluoro17(3-hydroxy-17u-ethyl-4-androsten-3-one 17- acetate.

8. 6a-fl1101'O-l7 B-hydroxy-17a-methy1-4-androsten-3-one.

9. fiat-fluoro-17,8-hydroxy-17a-methyl-4-androsten-3 0m 17-acetate.

10. 6 8-fluoro-l7/8-hydroxy-l7a-methyl-4 androsten 3- one.

11. 6/3-fluoro-17/3-hydroxy-17a-methyl-4 androsten 3- one l7-acetate.

l2. 3-oxygenated-6-fluoro-5,l7fl-dihydroxy-l7a alkylandrostanes of the following formula:

OH -"Ri OHa wherein R is selected from the group consisting of methyl and hydrogen, R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and R is selected from the group consisting of hydrogen and an alkyl radical containing from one to four carbon atoms, inclusive.

20. 6-fluoro-l7B-hydroxy-l7u-ethinyl-4-androsten-3-one.

21. o-fluoro-17/3-hydroxy-l7a-ethinyl-4androsten-3-one l7-acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

22. 6a-fluoro-17fi-hydroxy-l7a-ethinyl-4-androsten 3- one.

23. 6fl-fluoro-17fi-hydroxy-17u-ethinyl-4-androsten 3- one.

24. Goa-fluoro-17fl-hydroxy-l.7a-ethinyl-4-androsten3- one 17-acetate.

15 V" 16 25. 3-oxygenated-6-fluoro-5,17/8-dihydroxy-17a-ethiny1- 28. 313,175-dihydroxy-17 m-ethinyl 15,6 epoxyandrosandrostanes of the following formula: tanes of the following formula:

5 t CH; CH: i l OH OH 5 05cm ago R:

V R R HO Y wherein R is selected from the group consisting of methyl and hydrogen, and R is selected from the group consisting wherein R is selected from the group consisting of methyl of hydrogen and an alkyl radlcal contammg from one to four carbon atoms inclusive. and hydrogen, R 1s selected from the group eonslstlng of hydrogen and an alkyl radical containing from one to 3fi17fl'dmydmXy 17"ethmy1 epoxyandros' four carbon atoms, inclusive, and Y is selected from the 20 tame group consisting of hydroxy and ket References Cited in the file of this patent 26. 6 -fiuoro3 ,5 ,17 -tr1h dr -17 thn l d ostam 5 5 y 6 1 y an UNITED STATES PATENTS 27. 6fl-fluoro-5a,17fi-dihydroxy-17u-ethinylandrostan-3- 2,288,854 Stavely July 7, 1942 one. 2,332,815 Ruzicka Oct. 26, 1943 Disclaimer 2,838,500.J Allan OampbeZZ, Kalamazoo Township, Kalamazoo County,

Raymond L. Pedezson, Kalamazoo, J 07m 0. Babcock, Portage Township, Kalamazoo County, and J 07m A. H ogg Kalamazoo Township, Kalamazoo County, Mich. G-FLUORO STEROIDS. Patent dated June 10, 1958., Disclaimer filed May 20, 1965, by the inventors; the assignee, The U pjolm Company, assenting.

Hereby enter this disclaimer to claims 20, 22, 23, 26 and 27 of said patent.

[Ofiicial Gazette August 24, 1 965.]

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 2,838,500 I 10 1998 J Allen Campbell et a1 It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 14, line 38, for methylandrosten" read methylandrostan J Signed and sealed this 16th day of February 19600 (SEAL) Attest:

KARL H... AXLINE ROBERT C. WATSON Commissioner of Patents Attesting Officer UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,838,500 June 10, 1958 J Allan Campbell et a l.- It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 9, line 62, for procedure of Exam le 7 read procedure of Example 1; column 10, line 3, for 17-diaceta1] read -1 -diacetate]; line 10, for -methyl-4=- read -*-hydroXy-17a-methy1--&- column 16, lines 1 and 2, for -15,6-epoxyandrostanes read -5,6-ep0xyandr0stanes-.

Signed and sealed this 14th day of October 1958.

Attes't: KARL H. AXLINE, 1 ROBERT C. WATSON, Attesting Ofiioer. Oomam'ssz'omr of Patents. 

1. 6-FLUORO-17B-HYDROXY-17A-ALKYL-4-ANDROSTEN-3-ONES OF THE FOLLOWING FORMULA: 